PROJECT SUMMARY Cognitive deficits in individuals living with HIV can be debilitating and have a profound impact on long-term quality of life. The introduction of effective combinations of antiretroviral therapy (ART) has dramatically reduced the incidence of severe HIV-associated dementia (HAD), which was an early hallmark of the disease. Nevertheless, a spectrum of cognitive deficits remains for many individuals that are collectively classified as HIV-associated neurocognitive disorders (HAND). Strikingly, for many individuals, the emergence and severity of HAND appears to be independent of the effectiveness of ART in suppressing the virus. In addition, HIV is not thought to directly infect neurons in the central nervous system (CNS), further complicating our understanding of the underlying cause(s) of the cognitive deficits. One hypothesis is that ART itself has a deleterious or neurotoxic effect on neural cell types. Recent evidence based on analyses of postmortem tissue, and imaging studies supports this hypothesis and suggests that ART may induce changes in the CNS that could be relevant to the development of HAND. However, there is still a lack of data evaluating the direct effect these therapeutic drugs on human neurons and glia, due to the inaccessibility of these cell populations in individuals treated with ART. Based on recent advances in cellular reprogramming technology, we can now generate human induced pluripotent stem cells (iPSCs) derived from biospecimens obtained from consenting adults. These iPSCs can in turn be differentiated into most human cell types in the body, including those found in the CNS. Therefore, we now have a renewable source of human cells to model neurological function and disorders using relevant human cell types. In this project, we have assembled a multidisciplinary team of investigators to study the consequences of perinatal exposure to ART using an iPSC-based 3D model of human brain development. Successful completion of the proposed experiments will provide novel information on the direct effects of different classes of ART using relevant human cell types.